Diagnostic Accuracy and economic value of a Tiered Assessment for Fetal Alcohol Spectrum Disorder (DATAforFASD): Protocol

Introduction Australian practices for diagnosing fetal alcohol spectrum disorder (FASD) are lengthy and require specialist expertise. Specialist teams are based in urban locations; they are expensive and have prolonged waitlists. Innovative, flexible solutions are needed to ensure First Nations children living in rural/remote communities have culturally appropriate and equitable access to timely diagnosis and support. This study compares the accuracy of rapid assessments (index tests) that can be administered by a range of primary healthcare practitioners to specialist standardised FASD assessments (reference tests). The cost-efficiency of index tests will be compared with reference tests. Methods and analysis At least 200 children aged 6–16 years at-risk of FASD will be recruited across at least seven study sites. Following standards for reporting diagnostic accuracy study (STARD) guidelines, all children will complete index and reference tests. Diagnostic accuracy statistics (including receiver operating curves, sensitivity, specificity, positive and negative predictive values and likelihood ratios) will identify whether rapid assessments can accurately identify: (1) the presence of an FASD diagnosis and (2) impairment in each neurodevelopmental domain, compared to comprehensive assessments. Direct and indirect healthcare costs for index tests compared to reference tests will be collected in primary healthcare and specialist settings. Ethics and dissemination of results Children’s Health Queensland Hospital and Health Service Human Research Ethics Committee (HREC/20/QCHQ/63173); Griffith University Human Research Ethics Committee (2020/743). Results will assist in validating the use of index tests as part of a tiered neurodevelopmental assessment process that was co-designed with First Nations community and primary healthcare practitioners. Outcomes will be summarised and provided to participating practitioners and sites, and disseminated to community health services and consumers. Findings will be presented at national and international conferences and published in peer-reviewed journals. Trial registration number ACTRN12622000498796.


REVIEWER
Badry, DE University of Calgary, Faculty of Social Work REVIEW RETURNED 14-Feb-2023

GENERAL COMMENTS
This research protocol is exceptionally well articulated and related to the practical and economic benefit of engaging in FASD diagnosis activity within a primary health care arena. As noted, FASD diagnosis are expensive and occur within specialized clinics. At present no infrastructure exists within primary health care in Australia to undertake these assessments. The protocol identifies a robust series of measures appropriate to the research and has a capable team, clearly identifying the contributions of each member in the protocol. The literature is well utilized and appropriate to current practice and knowledge about FASD in practice and in primary health care. Ethical consent has been obtained including from representatives of the Traditional owners of the land. A critical need exists to embed FASD diagnosis within primary health care and the protocol argues that this is possible and has potential economic costs savings should FASD diagnosis become available through primary health care providers. A tiered assessment approach as indicated has great potential and practically, the plan includes the assessment of 200 children, recognizing that potential limits such as study participation. Further, some limitations may exist in accessing available health care resources, particularly in remote areas. The critical need for FASD diagnosis is highlighted and it is suggested that the potential exists for 55% of the sample to have FASD confirmed. The instrumentation proposed for the research is clearly identified and comprehensive, and identifies the rationale for each index test, all highly suitable for the protocol. The procedures are clearly identified for conducting the research and training for study protocols is included. The inclusion of an economic analysis is a distinct feature of the protocol and recognizes that there are direct and indirect costs associated with FASD diagnosis, including the costs to caregivers, which is rarely identified or recognized in the literature. Data analysis will take place via REDCap which appropriate and index tests will be compared with diagnostic outcomes in reference tests. Appropriate statistical analysis was identified for this research and results are pending following completion of the research. As a protocol it is evident that significant preparation has been undertaken and this is a sound research protocol. The research will be disseminated via publications and reports to the community. This protocol and paper is exceptionally written with no revisions recommended or required.

GENERAL COMMENTS
This is a well conceived, clearly presented protocol. The implications of this work would have wide interest to clinics involved in FASD diagnosis for exactly the reasons outlined in the work. The authors appear to have engaged meaningfully with First Nations/Indigenous groups in the development of the methods. Methodologic evaluation of the RNDA against gold standard battery of assessments for FASD as well as a broad economic cost analysis is appropriate and also well conceived. However, the choice of the RNDA is interesting --the original research was in Bangladesh with later studies in Guatemala, and I do not see studies that would relate this work to an Australian/first world context. I also did not find more recent study than 2016. The studies comment on the need for further validation and couch comments within a screening paradigm rather than a diagnostic application. I would thus be cautious in interpretation of what appears to be a screening tool compared to a diagnostic battery and the importance of differential diagnosis. Nevertheless, the introductory comments on the costs, waitlists, and resource intensity of FASD assessment are valid and this work will contribute to global considerations on efficient and accurate early diagnosis of this complex disorder. I will look forward to results from this study.

GENERAL COMMENTS
A couple of minor elucidations would help to clarify some points. First a brief explanation for why Brain Structure domains are not included. Second, additional details about who is conducting the caregiver interviews (or whether they will be done at the same time as the usual assessment).

Reviewer 1
Comment Response This research protocol is exceptionally well articulated and related to the practical and economic benefit of engaging in FASD diagnosis activity within a primary health care We would like to thank reviewer 1 for their positive feedback.
arena. As noted, FASD diagnosis are expensive and occur within specialized clinics. At present no infrastructure exists within primary health care in Australia to undertake these assessments. The protocol identifies a robust series of measures appropriate to the research and has a capable team, clearly identifying the contributions of each member in the protocol. As a protocol it is evident that significant preparation has been undertaken and this is a sound research protocol.
We would like to thank reviewer 1 for noticing the amount of preparation.

Reviewer: 2 Comment
Response This is a well-conceived, clearly presented protocol. The implications of this work would have wide interest to clinics involved in FASD diagnosis for exactly the reasons outlined in the work. The authors appear to have engaged meaningfully with First Nations/Indigenous groups in the development of the methods. Methodologic evaluation of the RNDA against gold standard battery of assessments for FASD as well as a broad economic cost analysis is appropriate and also well conceived.
We would like to thank reviewer 2 for their positive feedback.
The choice of the RNDA is interesting --the original research was in Bangladesh with later studies in Guatemala, and I do not see studies that would relate this work to an Australian/first world context. I also did not find more recent study than 2016. The studies comment on the need for further validation and couch comments within a screening paradigm rather than a diagnostic application.
Our team have administered the RNDA to around 900 Australian children, including remote and First Nations children. Preliminary evidence suggests the RNDA already functions well as a screening tool. We have included a recent citation of our use of the RNDA as a developmental screener in preventative health checks in the Australian context on page 11. Additional studies documenting reliability and validity in an Australian context are being prepared. The current diagnostic accuracy study will help us to further understand the sensitivity, specificity and diagnostic capacity of the RNDA in an Australian context.

Reviewer: 3 Comment
Response A brief explanation for why Brain Structure domains are not included.
A sentence has been added to page 7: The reference test for the brain structure domain is already rapid (i.e., history of seizures, head circumference or brain imaging if available). Therefore, an index test for this domain will not be administered. Information for this domain will still be collected for diagnostic purposes.
Additional details about who is conducting the caregiver interviews (or whether they will be done at the same time as the usual assessment) A sentence has been added to the methods section with additional details about who is conducting the caregiver interviews and when: Enrolled families and healthcare practitioners will complete surveys with one member from the research team that capture prospective cost information at the completion of testing.
Thank-you again for reviewing our manuscript. We look forward to the next steps in the publication journey.

GENERAL COMMENTS
Very clearly organized research. This work is of international interest and value to multidisciplinary diagnostic clinics faced with the challenges of long and complex assessments of brain domains as required by the various guidelines. By comparing index tests to gold standard appropriately there may be system benefits to individuals and families as well as cost savings as you have outlined. Will look forward to your results with interest.

Probert, Adam
Public Health Agency of Canada REVIEW RETURNED 14-Jul-2023

GENERAL COMMENTS
This is a well developed and written proposal. I appreciate the time and effort spent in revising . There is a critical need for this, and similar studies and we look forward to the results.